Production process for 16-dehydropregnenoneol and its analogs

ABSTRACT

The present invention relates to a clean process for the degradation of steroidal sapogenin to produce 16-dehydropregnenolone and its analogs. The pure or the crude pseudo steroidal sapogenin, derived from steroidal sapogenin, dissolved in organic solvent, reacts with hydrogen peroxide with or without metal compound and acid as catalyst, and the crude products directly go through elimination and hydrolization in the presence of base to give 16-Dehydropregnenolone or its analog, accompanied with the other product 4R(or S)-methyl-5-hydroxy-pentate, which is converted to 4R(or S)-methyl-δ-pentyl lactone after acidification and extraction from the water layer. This technology improved the utilizing degree of steroidal sapogenin, improved the yield, and cleared up the chromium pollution in the former technique. In a word, the method disclosed in this invention is more suitable for manufacture.

TECHNICAL FIELD

The invention relates to a clean process for the degradation ofsteroidal sapogenin to produce 16-dehydropregnenolone and its analogs.

BACKGROUND ART

16-Dehydropregnenolone (3β-hydroxypregn-5(6),16(17)-diene-20-one)is thehydrolysate of 16-Dehydropregnenolone acetate which is called ‘diene’ inindustry. Its analogs include 3β-hydroxy-5α-pregn-16(17)-ene-20-one,3β-hydroxy-5β-pregn-16(17)-ene-20-one,3β,12β-dihydroxy-5α-pregn-16(17)-ene-20-one,3β,12α-dihydroxy-5α-pregn-16(17)-ene-20-one,3β-hydroxy-5α-pregn-12,20-dione.

16-Dehydropregnenolone acetate and 3β-hydroxy-5α-pregn-16(17)-ene-20-oneacetate are important intermediates of steroidal hormone drugs. Thethroughput of the two compounds is kiloton and several hundred ton inChina each year, respectively.

But the technique of manufacturing the two compounds used today is stillbased on the old degradation method of steroidal sapogenin which wasdeveloped by Marker, an American chemist, in the 40′ last century(Marker: J. Am. Chem. Soc. 1940, 62, 3350. 1941, 63, 774. 1947, 692167). It can be described below: in acetic anhydride and acetic acid,under high pressure and at high temperature (above 200° C.), steroidalsapogenin is degradated to pseudo steroidal sapogenin, which is oxidizedby chromate. After elimination, the corresponding 16-Dehydropregnenoloneis obtained. The overall yield is about 60% for the three steps. Takingdiosgenin for example, it can be outlined below:

Though this method had been ameliorated successively, the shortcomingsstill exist. One of the shortcomings is the oxidation with chromate inthe procedure, which caused serious environmental pollution. Therefor,Professor Weisheng Tian and his co-workers had opened out the researchof how to utilize steroidal sapogenin rationally since 1991.

The present invention is the extending of Tian's prevenient inventions(Weisheng Tian, et al, Chinese patent, patent No: 96116304.6; Chinesepatent, application No: 00127974.2; Chinese patent, application No:01113196.9 etc).

ABSTRACT OF THE INVENTION

In this invention, the pseudo steroidal sapogenin, degradated fromsteroidal sapogenin without purification, is oxidized with hydrogenperoxide (instead of chromate) in organic solvent with or without metalcatalysts. After elimination and hydrolization, the corresponding16-Dehydropregnenolone or its analog is obtained. Another product, 4R(orS)-methyl-pentyl lactone, is produced in the process. The mentionedsteroidal sapogenin includes: diosgenin, tigogenin, sarsasapogenin,hecogenin, and other natural steroidal sapogenin. It also includes theanalogs modified from natural steroidal. The structure of16-dehydropregnenolone and its analogs can be outlined below:

DISCLOSURE OF THE INVENTION

The invention relates to a clean process for the degradation ofsteroidal sapogenin to produce 16-dehydropregnenolone and its analogs.

In this invention, the crude pseudo steroidal sapogenin, degradated fromsteroidal sapogenin, is oxidized with hydrogen peroxide in the presenceof metal catalysts. After elimination and hydrolization, thecorresponding 16-Dehydropregnenolone or its analog is obtained. Anotherproduct, 4R(or S)-methyl-pentyl lactone, is produced in the process.

In this invention, the pseudo steroidal sapogenin, degradated fromsteroidal sapogenin, is oxidized with hydrogen peroxide (instead ofchromate) in organic solvent with or without metal catalysts. Afterelimination and hydrolization, the corresponding 16-Dehydropregnenoloneor its analog is obtained. Another product, 4R(or S)-methyl-pentyllactone, is produced in the process. For example:

The operation of this invention is described below:

Firstly, steroidal sapogenin is degradated to pseudo steroidal sapogeninunder high pressure according to known method. Then, the pseudosteroidal sapogenin went through oxidation, elimination andhydrolization. 16-Dehydropregnenolone or its analog is obtained,accompanied with 4R(or S)-methyl-δ-pentyl lactone.

This invention is different from the patent CN: 01113196.9. The productdescribed in the patent CN: 01113196.9 is 16-Dehydropregnenoloneacetate, while it is 16-Dehydropregnenolone in this invention.

The crude degradation product is dissolved in organic solvent, and thenhydrogen peroxide, metal catalyst and acid are added. The molar ratio ofpseudo steroidal sapogenin, hydrogen peroxide, metal catalyst and acidis 1:1.0-4.0:0.001-1:0-1, of which 1:1.5-2.5:0.005-0.02:0 is preferred.The reaction temperature is 0-80° C. The reaction time is 10 min to 24hour. The reaction is monitored by chromatogram until the startingmaterial disappeared. The mixture is refluxed with base for 0.5-2 hourto completely convert the unreacted 16-carbonoxyl-20-one to16-Dehydropregnenolone or its analog, accompanied with the other product4R(or S)-methyl-5-hydroxy-pentate. Remove part of the organic solventunder reduced pressure then add water to precipitate16-Dehydropregnenolone or its analog. The water layer is acidified andextracted with organic solvent to give 4R(or S)-methyl-δ-pentyl lactone.

The mentioned steroidal sapogenin includes: diosgenin, tigogenin,sarsasapogenin, hecogenin, and other natural steroidal sapogenin. Italso includes the analogs modified from natural steroidal sapogenin.

The mentioned steroidal sapogenin is of the structure:

In which R or R′ is H or OH, C-5(6) and/or C-9(11) is C—C or C═C, C-25Ror C-25S, and C-5 is 5α-H or 5β-H when C-5(6) is C—C.

The structure of the mentioned 16-dehydropregnenolone and its analogscan be outlined below:

In which R or R′ is H or OH, C-5(6) and/or C-9(11) is C—C or C═C, andC-5 is 5α-H or 5β-H when C-5(6) is C—C.

The mentioned metal catalyst include: tungstic oxide (WO₃), tungstate,vanadic acid, vanadate, vanadyl acetylacetonate, molybdic anhydride(MoO₃), molybdate, phosphomolybdate, heteropolyacid, heteropolyate.

The mentioned acid include carboxylic acid, sulfonic acid and inorganicacid, where the carboxylic acid is preferable to be acetic acid, formicacid, propionic acid, butyric acid, benzoic acid, phthalic acid andisophthalic acid, the sulfonic acid is preferable to be benzenesulfonicacid and p-toluene sulphonic acid, and the inorganic acid is preferableto be sulfuric acid (H₂SO₄), phosphoric acid (H₃PO₄) and phosphorousacid (H₃PO₃).

The mentioned organic solvent include dihalogen methane, trihalogenmethane, dichloroethane, ethanol (EtOH), butanol (BuOH), t-butanol(t-BuOH), dimethyl sulphoxide (DMSO), N,N-dimethylformamide (DMF),acetone, butanone, cyclohexanone, acetonitrile, ethyl acetate and aceticacid.

The mentioned base include: hydroxid, carbonate and bicarbonate,preferably to be sodium hydroxide (NaOH), potassium hydroxide (KOH),lithium hydroxide (LiOH), cesium hydroxide (CsOH), sodium carbonate(Na₂CO₃), potassium carbonate (K₂CO₃), lithium carbonate (Li₂CO₃),cesium carbonate (Cs₂CO₃), sodium bicarbonate (NaHCO₃) and potassiumbicarbonate (KHCO₃).

This invention had been verified in hundred-gram scale for severaltimes. This technology improved the utilizing degree of steroidalsapogenin, improved the yield, and cleared up the chromium pollution informer technique. In a word, the method disclosed in this invention ismore suitable for manufacture.

EXAMPLES

The invention is illustrated below with reference to the followingexamples. Other features of the invention will become apparent in thecourse of the following descriptions of exemplary embodiments that aregiven for illustration of the invention and are not intended to belimiting thereof.

Example 1 Degradation of sarsasapogenin to3β-hydroxy-5β-pregn-16(17)-ene-20-one and 4S-methyl-δ-pentyl lactone

10 g of sarsasapogenin, dissolved in acetic acid and acetic anhydride,was kept in the pressure kettle at 200° C. for one hour, then 3.3 mg ofNa₂WO₄.2H₂O (0.01 mmol) and 5 ml of hydrogen peroxide (30% H₂O) wereadded, and this mixture was stirred for 2 hours at 80° C. The lowboilers were removed under reduced pressure and the residue wasdissolved in 50 ml of EtOH, and refluxed for 2 hours with 5% LiOH. Themixture was concentrated, diluted with water, and filtrated to get 6.3 gof 3β-hydroxy-5β-pregn-16(17)-ene-20-one in 84% yield. m.p. 186-8° C.,¹H-NMR (300 MHz, CDCl₃) δ(ppm): 6.61 (dd, J=1.3 Hz, 1H, 16-H), 3.5 (m,1H, 3-H), 2.26 (s, 3H, CH₃CO—, 21-H), 0.84 (s,3H, 18-H), 0.88 (s, 3H,19-H). MS (m/z, %): 316 (M⁺), 301 (M⁺-CH₃), 283 (M⁺-CH₃— H₂O), 159, 145,115, 105, 91, 43. The water layer was acidified and extracted withorganic solvent to give 2.1 g of 4S-methyl-δ-pentyl lactone in 80%yield. [α]²⁰ _(D)=−13° (c 0.8, CHCl₃), IR(v): 2950, 1730, 1340, 1210,1190, 1040 cm⁻¹. ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.96 (d, 3H, J=6.6 Hz),1.88-2.06 (m, 2H), 1.43-1.56 (m, 1H), 3.83-3.90 (m, 1H), 4.23-4.29 (m,1H). MS (m/z, %): 115 (M⁺+1), 114 (M⁺), 109, 56, 42.

Example 2 Degradation of sarsasapogenin to3β-hydroxy-5β-pregn-16(17)-ene-20-one and 4S-methyl-δ-pentyl lactone:

100 g of sarsasapogenin, dissolved in acetic acid and acetic anhydride,was kept in the pressure kettle at 200° C. for one hour, then the lowboilers were removed under reduced pressure and the residue wasdissolved in 500 ml of BuOH. 23 mg of WO₃ (0.01 mmol), 10 g ofisophthalic acid and 50 ml of hydrogen peroxide (30% H₂O) were added,and this mixture was stirred for 2 hours at 80° C. After 5% KOH wasadded, it was kept on refluxing for 2 hours. The mixture wasconcentrated, diluted with water, and filtrated to get 66 g of3β-hydroxy-5β-pregn-16(17)-ene-20-one in 88% yield. The water layer wasacidified and extracted with organic solvent to give 22 g of4S-methyl-δ-pentyl lactone in 84% yield.

Example 3 Degradation of sarsasapogenin to3β-hydroxy-5β-pregn-16(17)-ene-20-one and 4S-methyl-δ-pentyl lactone:

100 g of sarsasapogenin, dissolved in acetic acid and acetic anhydride,was kept in the pressure kettle at 200° C. for one hour, then the lowboilers were removed under reduced pressure and the residue wasdissolved in 500 ml of BuOH. 23 mg of WO₃ (0.01 mmol), 1 g ofisophthalic acid and 50 ml of hydrogen peroxide (30% H₂O) were added,and this mixture was stirred for 2 hours at 80° C. After 5% KOH wasadded, it was kept on refluxing for 2 hours. The mixture wasconcentrated, diluted with water, and filtrated to get 60 g of3β-hydroxy-5β-pregn-16(17)-ene-20-one in 80% yield. The water layer wasacidified and extracted with organic solvent to give 22 g of4S-methyl-δ-pentyl lactone in 84% yield.

Example 4 Degradation of diosgenin to 16-dehydropregnenolone and4R-methyl-δ-pentyl lactone

100 g of diosgenin, dissolved in acetic acid and acetic anhydride, waskept in the pressure kettle at 200° C. for one hour, then 3.3 mg of(NH₄)₂MoO₄ (0.01 mmol), 5 g of benzoic acid and 50 ml of hydrogenperoxide (30% H₂O) were added, and this mixture was stirred for 2 hoursat 80° C. The low boilers were removed under reduced pressure and theresidue was dissolved in 500 ml of cyclohexatone, and refluxed for 2hours with 5% CsOH. The mixture was concentrated, diluted with water,and filtrated to get 64 g of 16-dehydropregnenolone in 84% yield. m.p.168-170° C., ¹H-NMR (300 MHz, CDCl₃)δ(ppm): 6.72 (dd, J=1.3 Hz, 1H,16-H), 5.38 (d, J=4Hz, 1H, 6-H), 2.26 (s, 3H, CH₃CO—, 21-H), 0.85 (s,3H, 18-H), 0.88 (s, 3H, 19-H). MS (m/z, %): 314 (M⁺), 299 (M⁺-CH₃), 281(M⁺-CH₃—H₂O), 253, 239, 229, 203, 159, 145, 115, 105, 91, 43. The waterlayer was acidified and extracted with organic solvent to give 22 g of4R-methyl-δ-pentyl lactone in 80% yield. b.p. 83-89° C./15 mmHg, [α]²⁰_(D)=+13.6° (c 0.9 CHCl₃), IR(v): 2950, 1730, 1340, 1210, 1190, 1040cm⁻¹. ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.96 (d, 3H, J=6.6 Hz), 1.88-2.06(m, 2H), 1.43-1.56 (m, 1H), 3.83-3.90 (m, 1H), 4.23-4.29 (m, 1H).MS(m/z, %): 115 (M⁺+1), 114 (M⁺), 109, 56, 42.

Example 5 Degradation of diosgenin to 16-dehydropregnenolone and4R-methyl-δ-pentyl lactone

100 g of diosgenin, dissolved in acetic acid and acetic anhydride, waskept in the pressure kettle at 200° C. for one hour, then the lowboilers were removed under reduced pressure and the residue wasdissolved in 500 ml of EtOH. 182 mg of ammonium phosphomolybdate((NH₄)₃[P(Mo₁₂O₄₀)].6H₂O, 0.1 mmol) and 50 ml of hydrogen peroxide (30%H₂O) were added, and this mixture was stirred for 2 hours at 80° C.After NaHCO₃ was added, it was kept on refluxing for 2 hours. Themixture was concentrated, diluted with water, and filtrated to get 72 gof 16-dehydropregnenolone in 95% yield. The water layer was acidifiedand extracted with organic solvent to give 24 g of 4R-methyl-δ-pentyllactone in 88% yield.

Example 6 Degradation of diosgenin to 16-dehydropregnenolone and4R-methyl-δ-pentyl lactone

100 g of diosgenin, dissolved in acetic acid and acetic anhydride, waskept in the pressure kettle at 200° C. for one hour, then the lowboilers were removed under reduced pressure and the residue wasdissolved in 500 ml of EtOH. 3.48 g of VO(acac)₂ and 50 ml of hydrogenperoxide (30% H₂O) were added, and this mixture was stirred for 2 hoursat 80° C. After NaHCO₃ was added, it was kept on refluxing for 2 hours.The mixture was concentrated, diluted with water, and filtrated to get71 g of 16-dehydropregnenolone in 93% yield. The water layer wasacidified and extracted with organic solvent to give 24 g of4R-methyl-δ-pentyl lactone in 88% yield.

Example 7 Degradation of diosgenin to 16-dehydropregnenolone and4R-methyl-δ-pentyl lactone

10 g of diosgenin, dissolved in acetic acid and acetic anhydride, waskept in the pressure kettle at 200° C. for one hour, then the lowboilers were removed under reduced pressure and the residue wasdissolved in 50 ml of dichloromethane. 18 mg of (NH₄)₃[P(Mo₁₂O₄₀)].6H₂O(0.1 mmol) and 5 ml of hydrogen peroxide (30% H₂O) were added, and thismixture was refluxed for 2 hours. After K₂CO₃ was added, it was kept onrefluxing for 2 hours. The mixture was concentrated, diluted with water,and filtrated to get 7.2 g of 16-dehydropregnenolone in 95% yield. Thewater layer was acidified and extracted with organic solvent to give 2.4g of 4R-methyl-δ-pentyl lactone in 88% yield.

Example 8 Degradation of diosgenin to 16-dehydropregnenolone and4R-methyl-δ-pentyl lactone

100 g of diosgenin, dissolved in acetic acid and acetic anhydride, waskept in the pressure kettle at 200° C. for one hour, then the lowboilers were removed under reduced pressure and the residue wasdissolved in 500 ml of t-BuOH. 23 mg of WO₃, 2 ml of H₃PO₄ and 50 ml ofhydrogen peroxide (30% H₂O) were added, and this mixture was stirred for2 hours at 80° C. After KOH was added, it was kept on refluxing for 2hours. The mixture was concentrated, diluted with water, and filtratedto get 70 g of 16-dehydropregnenolone in 92% yield. The water layer wasacidified and extracted with organic solvent to give 23 g of4R-methyl-δ-pentyl lactone in 84% yield.

Example 9 Degradation of tigogenin to3β-hydroxy-5α-pregn-16(17)-ene-20-one and 4R-methyl-δ-pentyl lactone

100 g of tigogenin, dissolved in acetic acid and acetic anhydride, waskept in the pressure kettle at 200° C. for one hour, then the lowboilers were removed under reduced pressure and the residue wasdissolved in 500 ml of BuOH. 200 mg of Na₃[P(W₁₂O₄₀)] and 50 ml ofhydrogen peroxide (30% H₂O) were added, and this mixture was stirred for2 hours at 80° C. After NaOH was added, it was kept on refluxing for 2hours. The mixture was concentrated, diluted with water, and filtratedto get 70 g of 3β-hydroxy-5α-pregn-16(17)-ene-20-one in 92% yield. m.p.207-9° C., [α]²⁰ _(D)=+51° (c 0.9 CHCl₃), ¹H-NMR (300 MHz, CDCl₃)δ(ppm):6.59 (dd, J=1.3 Hz, 1H, 16-H), 3.45 (m, 1H, 3-H), 2.26 (s, 3H, CH₃CO—,21-H), 0.83 (s, 3H, 18-H), 0.89 (s, 3H, 19-H). MS (m/z, %): 316 (M⁺),301 (M⁺-CH₃), 283 (M⁺-CH₃—H₂O), 159, 145, 115, 105, 91, 43. The waterlayer was acidified and extracted with organic solvent to give 21 g of4R-methyl-δ-pentyl lactone in 80% yield.

Example 10 Degradation of tigogenin to3β-hydroxy-5α-pregn-16(17)-ene-20-one and 4R-methyl-δ-pentyl lactone

10 g of tigogenin, dissolved in acetic acid and acetic anhydride, waskept in the pressure kettle at 200° C. for one hour, then the lowboilers were removed under reduced pressure and the residue wasdissolved in 50 ml of DMF. 48 mg of Na₂MoO₄.2H₂O (0.2 mmol), 0.1 ml ofH₂SO₄ and 5 ml of hydrogen peroxide (30% H₂O) were added, and thismixture was stirred for 2 hours at 80° C. After KOH was added, it waskept on stirring for 2 hours at 80° C. The mixture was diluted withwater and filtrated to get 6.8 g of3β-hydroxy-5α-pregn-16(17)-ene-20-one in 90% yield. The water layer wasacidified and extracted with organic solvent to give 2.3 g of4R-methyl-δ-pentyl lactone in 84% yield.

Example 11 Degradation of tigogenin to3β-hydroxy-5α-pregn-16(17)-ene-20-one and 4R-methyl-δ-pentyl lactone

100 g of tigogenin, dissolved in acetic acid and acetic anhydride, waskept in the pressure kettle at 200° C. for one hour, then 186 mg ofH₇[(PMo₂O₇)₆].xH₂O (0.1 mmol) and 50 ml of hydrogen peroxide (30% H₂O)were added, and this mixture was stirred for 2 hours at 80° C. The lowboilers were removed under reduced pressure and the residue wasdissolved in 500 ml of EtOH containing 5% KOH, and refluxed for 2 hours.The mixture was concentrated, diluted with water, and filtrated to get65 g of 3β-hydroxy-5α-pregn-16(17)-ene-20-one in 86% yield. The waterlayer was acidified and extracted with organic solvent to give 22 g of4R-methyl-δ-pentyl lactone in 80% yield.

Example 12 Degradation of rockogenin to3β,12β-dihydroxy-5α-pregn-16(17)-ene-20-one and 4R-methyl-δ-pentyllactone

100 g of rockogenin, dissolved in acetic acid and acetic anhydride, waskept in the pressure kettle at 200° C. for one hour, then the lowboilers were removed under reduced pressure and the residue wasdissolved in 500 ml of BuOH. 30 mg of V₂O₅(0.2 mmol), 1 ml ofphosphorous acid and 50 ml of hydrogen peroxide (30% H₂O) were added,and this mixture was stirred for 2 hours at 80° C. After KOH was added,it was kept on refluxing for 2 hours. The mixture was concentrated,diluted with water, and filtrated to get 70 g of3β,12β-dihydroxy-5α-pregn-16(17)-ene-20-one in 91% yield. m.p. 203-205°C., [α]_(D) ²⁵=+2.0 (c=1.00 CHCl₃),IR(v): 1645, 1580 cm⁻¹, ¹H-NMR (300MHz, CDCl₃) δ(ppm): 6.90 (m, 1H, 16-H), 2.37 (s, 3H, CH₃CO—, 21-H), 0.87(s, 3H, 18-H), 0.82 (s, 3H, 19-H). The water layer was acidified andextracted with organic solvent to give 23 g of 4R-methyl-δ-pentyllactone in 84% yield.

Example 13 Degradation of rockogenin to3β,12β-dihydroxy-5α-pregn-16(17)-ene-20-one and 4R-methyl-δ-pentyllactone

100 g of rockogenin, dissolved in acetic acid and acetic anhydride, waskept in the pressure kettle at 200° C. for one hour, then the lowboilers were removed under reduced pressure and the residue wasdissolved in 500 ml of BuOH. 30 mg of MoO₃, 1 ml of phosphorous acid and50 ml of hydrogen peroxide (30% H₂O) were added, and this mixture wasstirred for 3 hours at 80° C. After KOH was added, it was kept onrefluxing for 2 hours. The mixture was concentrated, diluted with water,and filtrated to get 70 g of 3β,12β-dihydroxy-5α-pregn-16(17)-ene-20-onein 91% yield. The water layer was acidified and extracted with organicsolvent to give 23 g of 4R-methyl-δ-pentyl lactone in 84% yield.

Example 14 Degradation of rockogenin to3β,12β-dihydroxy-5α-pregn-16(17)-ene-20-one and 4R-methyl-δ-pentyllactone

100 g of rockogenin, dissolved in acetic acid and acetic anhydride, waskept in the pressure kettle at 200° C. for one hour, then the lowboilers were removed under reduced pressure and the residue wasdissolved in 500 ml of BuOH. 30 mg of WO₃(0.2 mmol), 1 ml of phosphorousacid and 50 ml of hydrogen peroxide (30% H₂O) were added, and thismixture was stirred for 2 hours at 80° C. After KOH was added, it waskept on refluxing for 2 hours. The mixture was concentrated, dilutedwith water, and filtrated to get 71 g of3β,12β-dihydroxy-5α-pregn-16(17)-ene-20-one in 92% yield. The waterlayer was acidified and extracted with organic solvent to give 23 g of4R-methyl-δ-pentyl lactone in 84% yield.

Example 15 Degradation of rockogenin to3β,12β-dihydroxy-5α-pregn-16(17)-ene-20-one and 4R-methyl-δ-pentyllactone

10 g of rockogenin, dissolved in acetic acid and acetic anhydride, waskept in the pressure kettle at 200° C. for one hour, then the lowboilers were removed under reduced pressure and the residue wasdissolved in 50 ml of DMSO. 24 mg of Na₂MoO₄.2H₂O (0.1 mmol), 1 ml ofH₃PO₄ and 5 ml of hydrogen peroxide (30% H₂O) were added, and thismixture was stirred for 2 hours at 80° C. After Li₂CO₃ was added, it waskept on stirring for 2 hours at 80° C. The mixture was diluted withwater and filtrated to get 7.2 g of3β,12β-dihydroxy-5α-pregn-16(17)-ene-20-one in 94% yield. The waterlayer was acidified and extracted with organic solvent to give 2.4 g of4R-methyl-δ-pentyl lactone in 88% yield.

Example 16 Degradation of rockogenin to3β,12β-dihydroxy-5α-pregn-16(17)-ene-20-one and 4R-methyl-δ-pentyllactone

10 g of rockogenin, dissolved in acetic acid and acetic anhydride, waskept in the pressure kettle at 200° C. for one hour, then the lowboilers were removed under reduced pressure and the residue wasdissolved in 50 ml of DMSO. 24 mg of Na₂MoO₄.2H₂O (0.1 mmol), 1 g ofbutyric acid and 5 ml of hydrogen peroxide (30% H₂O) were added, andthis mixture was stirred for 2 hours at 80° C. After Li₂CO₃ was added,it was kept on stirring for 2 hours at 80° C. The mixture was dilutedwith water and filtrated to get 7.2 g of3β,12β-dihydroxy-5α-pregn-16(17)-ene-20-one in 94% yield. The waterlayer was acidified and extracted with organic solvent to give 2.4 g of4R-methyl-δ-pentyl lactone in 88% yield.

1. A clean technology of producing 16-dehydropregnenolone and itsanalogs, that is, the pure or the crude pseudo steroidal sapogenin,derived from steroidal sapogenin, dissolved in organic solvent, reactswith hydrogen peroxide for 0.5-24 h at 0-80° C. with/without metalcompound and acid as catalyst, wherein the molar ratio of pseudosteroidal sapogenin, hydrogen peroxide, metal catalyst and acid is1:1.0-4.0:0.001-1:0-1, of which 1:1.5-2.5:0.005-0.02:0 is preferred, andthe base is added to the mixture and then the mixture is kept at 0-100°C. or in reflux for 0.5-2 hour to give 16-Dehydropregnenolone or itsanalog, accompanied with the other product 4R(orS)-methyl-5-hydroxy-pentate, which is converted to 4R(orS)-methyl-δ-pentyl lactone after acidification and extraction from thewater layer. The mentioned steroidal sapogenin is of the structure:

in which R or R′ is H or OH, C-5(6) and/or C-9(11) is C—C or C═C, C-25Ror C-25S, and C-5 is 5α-H or 5β-H when C-5(6) is C—C. The structure ofthe mentioned 16-dehydropregnenolone and its analogs can be outlinedbelow:

in which R or R′ is H or OH, C-5(6) and/or C-9(11) is C—C or C═C, andC-5 is 5α-H or 5β-H when C-5(6) is C—C. The mentioned metal catalystinclude: tungstic oxide, tungstate, vanadic acid, vanadate, vanadylacetylacetonate, molybdic anhydride, molybdate, phosphomolybdate,heteropolyacid and heteropolyate. The mentioned acid include carboxylicacid, sulfonic acid and inorganic acid, where the carboxylic acid ispreferable to be acetic acid, formic acid, propionic acid, butyric acid,benzoic acid, phthalic acid and isophthalic acid, the sulfonic acid ispreferable to be benzenesulfonic acid and p-toluene sulphonic acid, andthe inorganic acid is preferable to be sulfuric acid, phosphoric acidand phosphorous acid. The mentioned organic solvent include dihalogenmethane, trihalogen methane, dichloroethane, ethanol, butanol,t-butanol, dimethyl sulphoxide, N,N-dimethylformamide, acetone,butanone, cyclohexanone, acetonitrile, ethyl acetate and acetic acid.The mentioned base include: hydroxid, carbonate and bicarbonate,preferably to be sodium hydroxide, potassium hydroxide, lithiumhydroxide, cesium hydroxide, sodium carbonate, potassium carbonate,lithium carbonate, cesium carbonate, sodium bicarbonate and potassiumbicarbonate.
 2. A process as defined in claim 1, wherein the steroidalsapogenin is diosgenin, tigogenin, sarsasapogenin, hecogenin, the othernatural steroidal sapogenin or the analogs modified from naturalsteroidal sapogenin.
 3. A process as defined in claim 1, wherein themolar ratio of pseudo steroidal sapogenin, hydrogen peroxide, metalcatalyst and acid is 1:1.0-4.0:0.001-1:0-1, of which1:1.5-2.5:0.005-0.02:0 is preferred.
 4. A process as defined in claim 1,wherein 16-Dehydropregnenolone or its analog is obtained as precipitateafter water was added to the reaction mixture and the water layer isacidified and extracted with organic solvent to give 4R(orS)-methyl-δ-pentyl lactone.